Molecular and cellular study of the human cellular aging factors

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Normal human diploid fibroblasts have a limited proliferative capacity in vitro. In contrast, cells derived from tumors often exhibit unlimited proliferative potential (immortality). Immortalization of the human cells is associated with the process of cellular aging. We established an immortalization sensitive cell line from the fibroblasts of Wilms' tumor patients with a partial deletion of chromosome 11p. This cell line showed 50 times higher imortalization frequency than normal human fibroblasts immortalized by SV40T. This type of 11p-cells which produced SV40T protein showed an abnormal crisis at the senescent period, whereas T-antigen positive normal cells did not. The crisis culture of this 11p-cells showed a extremely higher frequency of spontaneous mutation and chromosomal aberrations than normal cells. By differential hybridization, we tried to identify the human genes that would be preferentially expressed in 11p-cells at the time of the crisis, and obtained a clone, C-1 gene, that was up-regulated in the senescent cells. A partial loss of C-1 gene was found in some kinds of immortal cells. These results indicate that the inactivation of senescent genes at the crisis phase of the cellular aging may be associated with the cellular immortalization.